This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. HIV-related brain disease has been linked to HIV's ability to grow in microglia (MG), cells residing in the central nervous system (CNS) and originating from bone marrow. We postulate that the ability of HIV to replicate efficiently in MG represents a hallmark of AIDS-associated brain disease. We further postulate that the HIV envelope gene that has been adapted to cultured human MG will confer the ability to cause brain disease to a simian-human immunodeficiency virus (SHIV) that contains this gene. SHIVs are hybrid viruses that are part SIV and part HIV, including the HIV envelope gene. We have constructed SHIV-Bo159N4, which contains the envelope gene of a primary HIV strain that had been adapted to human MG. We inoculated several monkeys with SHIV-Bo159N4 using cell-free virus or virus-infected MG. To augment viral replication in the blood and CNS, we simultaneously ablated CD8+ cells as well as B cells in the recipients. The SHIV-infected monkeys were followed for viral, hematological and neurological parameters. Some animals progressed to disease rapidly;their brain sections are undergoing neuropathological analysis. In a separate study, we observed disease progression with neurological complications in a Chinese-origin rhesus monkey infected with an R5-tropic clade C SHIV. A detailed analysis of this case revealed AIDS and infection of the optic nerve with two different viruses, including the SHIV.